Cognitive Impairment in Neuromuscular Diseases: A Systematic Review

Marco Orsini, Ana Carolina Andorinho de F. Ferreira, Anna Carolina Damm de Assis, Thais Magalhães, Silmar Teixeira, Victor Hugo Bastos, Victor Marinho, Thomaz Oliveira, Rossano Fiorelli, Acary Bulle Oliveira, Marcos R.G. de Freitas
Affiliations include:
- Master's Program in Health Applied Sciences, Severino Sombra University, Vassouras, Rio de Janeiro
- Brain Mapping and Plasticity Laboratory, Federal University of Piauí, Parnaíba
- Department of Neurology, Federal Fluminense University, Rio de Janeiro
- Department of Neurology, Federal University of São Paulo
- Department of Neurology, Federal University of Rio de Janeiro, Brazil

Neuromuscular Diseases (NMDs): Multifactorial pathologies characterized by muscle fiber damage, leading to satellite cell activation and exhaustion, impacting neurobiological functions including cognition and motor control.
Objective: To systematically review cognitive impairment in neuromuscular diseases.
Methods: Literature search conducted until October 2017 including experimental studies, case reports, and reviews in English.
Key Findings: Cognitive deficits associated with congenital molecular alterations in neuromuscular diseases could guide patient management, prognosis, treatment choices, and innovative gene therapies.

Cognitive effects of neuromuscular diseases (NMD) are understudied compared to their motor impacts.
Although NMD primarily affect motor functions, significant cognitive dysfunctions can arise from molecular defects affecting both neuromotor function and neural networks involved in cognitive processes.
Examples: Mutations in dystrophin gene causing Duchenne Muscular Dystrophy (DMD) also influence cognitive stability and CNS functions.
Major NMD groups linked to cognitive alterations:
1. Motor Neuron Diseases (MNDs)
2. Muscular Dystrophies (primarily dystrophinopathies)
3. Mitochondrial Disorders.

Systematic Review Process: Conducted following PRISMA guidelines; search involved ISI Web of Science and PubMed using terms like "Cognitive Impairment and Neuromuscular Diseases".
Inclusion Criteria:
- Studies reporting experimental work, case reports, or reviews published in English.
- No restrictions on publication date.
- Focus on studies using cognitive and functional scales, MRI assessments, and experimental studies with rat models.
Exclusion Criteria: Dissertations, book reviews, editorials could not be included.
Outcome Measures: Cognitive assessment methods included multiple established cognitive scales (e.g. MMSE, ACE-R, Wechsler tests).

From 80 studied papers, 63 met inclusion criteria:
- 17 experimental studies
- 30 case reports focused on cognitive assessments and NMD
- 16 review papers discussing neuropsychological aspects in NMD.
General findings: Patients exhibited executive dysfunction, shorter survival times, and significant cognitive performance impairment across a broad range of functions, such as memory and executive functioning.
Studies suggest cognitive deficits correlate poorly with muscular impairment, implicating brain regulation mechanisms in cognitive performance.

MND Overview: Degenerative disorders impacting lower and upper motor neurons; ALS is the most notable form.
Behavioral changes linked to MND often indicate higher care demands and predict disease progression.
Key Findings: Up to 50% of ALS patients may develop cognitive or behavioral impairments during the disease course. Categories of cognitive deficits exist within ALS populations, such as executive dysfunction and behavioral variants of frontotemporal dementia (bvFTD).
Noteworthy is that neuroimaging often fails to diagnose cognitive deficits unless significant pathology occurs.
Genetic Insights: The C9orf72 gene repeat expansion correlates with familial MND and FTD and is linked to changes in neuroinflammation and cognitive outcomes.
Specific Conditions: Kennedy’s Disease exemplifies an MND with varying levels of cognitive impairment, particularly impacting memory and executive functions. Most common manifestations included gynecomastia and reduced fertility alongside cognitive deficits.

Congenital Muscular Dystrophies (CMDs): Characterized by variable muscle weakness and associated cognitive impairments.
Notable findings in IQ assessments, where a significant number of subjects demonstrated lower IQs linked to specific gene mutations, particularly in dystrophinopathies (such as DMD).
Neuroimaging studies suggest various brain abnormalities corresponding to muscle impairment severity and may be indicative of deteriorating cognitive functions over time.

Mitochondrial diseases often present with CNS involvement, leading to cognitive decline through various forms of dementia.
Common syndromes such as MELAS and MERRF illustrate the relationship between mitochondrial function and cognitive health.
Cognitive evaluations reveal deficits in areas such as memory, language, and executive functions, with varying presentations based on specific mitochondrial mutations.

The literature indicates a robust link between neuromuscular diseases and cognitive impairment. Comprehensive assessments, including cognitive evaluations and patient history, are critical for optimizing patient management and improving quality of life.
Continued research is necessary to enhance our understanding of cognitive functions in NMD, refine evaluation methods, and develop targeted therapies to address both cognitive and physical impairments. Further studies are needed to standardize assessment protocols in cognitive evaluations across different populations.

A comprehensive list of references supporting the study's findings will be included, providing sources for data on cognitive evaluations, genetic studies, and specific examples of the aforementioned syndromes.